Normal repolarization of cardiac action potentials requires activation of the delayed rectifier K+ current, IKr. Block of IKr by certain medications causes long QT syndrome (LQT). The human IKr channel is encoded by the gene HERG, mutations in which are associated with inherited LQT. Both inherited and acquired LQT confer a predisposition to the potentially fatal cardiac arrhythmia torsade de pointes, an arrhythmia exacerbated by hypokalemia. A study of HERG K+ channel function will lead to a better understanding of the molecular mechanisms of these arrhythmias. HERG channels are characterized by two unusual properties: (1) The amplitude of HERG current is paradoxically increased by elevation of extracellular K+, despite the decrease in transmembrane chemical gradient. Although the mechanism of this effect is unknown, this property was utilized in a recent clinical study where it was demonstrated that an increase in serum [K+l normalized QT intervals in individuals with inherited LQT. (2) The magnitude of HERG channel current is reduced at increasingly positive potentials (rectification), despite the increase in transmembrane electrical gradient. Although they have shown that fast inactivation is the cause of rectification the molecular mechanism of inactivation is unknown. The applicants will determine the mechanism of [K+]-dependent modulation, and voltage-dependent fast inactivation of HERG channels expressed in Xenopus oocytes. The effect of [K+]e on HERG inactivation, gating current and single channel properties will be determined using wild-type HERG and in an inactivation-removed HERG mutant. These studies will define the molecular mechanisms of HERG channel function important for normal cardiac repolarization. (End of Abstract)